The applicant proposes a program of research to prepare him for a career in laboratory investigation of gastrointestinal malignancies. The research will be conducted in the laboratory of Dr. Daniel Haber at Massachusetts General Hospital. The applicant will study the genetic basis of cancer progression, which has broad implications in the understanding of cancer biology and the development of normal therapeutic targets. The research environment and the collaborations the applicant has established will provide excellent opportunities for his training and development as an independent scientist. Cancer progression, characterized by the penetration of basement membrane, angiogenesis and distant metastasis, is believed to occur as a result of accumulation of somatic mutations in the cancer genome. The overall goal of this project is to identify novel genes involved in cancer progression. Representational difference analysis (RDA) is a technique that combines principles of subtractive hybridization with PCR, thus, small genetic differences in cancer genomes, when compared with normal genomes, are readily amplified. Our preliminary results show that the direct use of RDA on human cancer specimens is limited by common polymorphic deletions. However, RDA on cancer cell lines derived from inbred mouse tumor models dramatically enhances the ability of detect pathological deletions. A region of homozygous deletion in a mouse osteosarcoma cell line has been identified and has led to the positional cloning of a candidate tumor suppressor gene. Experiments are aimed to search for mutations and elucidate the biological function of the candidate tumor suppressor gene in human and mouse cancer. This work will further our understanding of the genetic basis of cancer progression.